Abstract
The general mechanism involved in Tat activation of RNA Polymerase II (RNAP II) elongation of the integrated HIV-1 was elucidated over 20 years ago. This mechanism involves Tat binding to the TAR RNA element that forms at the 5’ end of viral transcripts and recruiting a general RNAP II elongation factor termed as PTEFb. This elongation factor consists of CDK9 and Cyclin T1, and when recruited by Tat to TAR RNA, CDK9 was proposed to phosphorylate the carboxyl terminal domain of RNAP II and thereby activate elongation. Research in the past two decades has shown that the mechanism of Tat action is considerably more complicated than this simple model. In metabolically active cells, CDK9 and Cyclin T1 are now known to be largely sequestered in a RNA-protein complex termed the 7SK RNP. CDK9 and Cyclin T1 are released from the 7SK RNP by mechanisms not yet fully elucidated and along with Tat, bind to TAR RNA and orchestrate the assembly of a Super Elongation Complex (SEC) containing several additional proteins. CDK9 in the SEC then phosphorylates multiple substrates in the RNAP II complex to activate elongation. Importantly for therapeutic strategies, CDK9 and Cyclin T1 functions are down-regulated in resting CD4+ T cells that harbor latent HIV-1, and their up-regulation is required for reactivation of latent virus. Current strategies for a functional cure of HIV-1 infection therefore are likely to require development of latency reversal agents that up-regulate CDK9 and Cyclin T1 function in resting CD4+ T cells.
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